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 Prepublished online as a Blood First Edition Paper on April 24, 2003; DOI 10.1182/blood-2002-09-2974.

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2002-09-2974v1
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Blood, 15 August 2003, Vol. 102, No. 4, pp. 1480-1489

NEOPLASIA

The coupling of TEL/PDGF{beta}R to distinct functional responses is modulated by the presence of cytokine: involvement of mitogen-activated protein kinases

Helen Wheadon, and Melanie J. Welham

From the Department of Pharmacy and Pharmacology, University of Bath, United Kingdom.

The TEL/PDGF{beta}R oncogenic fusion protein is the product of the t(5;12)(q33; p13) translocation recurrently found in patients with chronic myelomonocytic leukemia (CMML). To investigate the coupling of molecular signaling events activated by TEL/PDGF{beta}R to functional responses, we expressed TEL/PDGF{beta}R in interleukin 3 (IL-3)–dependent BaF/3 cells using the tetracycline-regulated expression system. Induction of TEL/PDGF{beta}R expression led to increased cell survival following IL-3 withdrawal and constitutive activation of protein kinase B (PKB), signal transducer and activator of transcription 5 (STAT5), extracellular signal-regulated kinases 1/2 (ERK1/2), Jun N-terminal kinases 1/2 (JNK1/2), and p38 mitogenactivated protein kinase (MAPK) pathways. However, inducible expression of TEL/PDGF{beta}R failed to generate factor-independent cells, whereas constitutive expression of TEL/PDGF{beta}R did, albeit at low frequency, suggesting the duration of TEL/PDGF{beta}R expression is important for transformation. Surprisingly, in cells induced to express TEL/PDGF{beta}R, IL-3–dependent growth was dramatically reduced as a result of increased apoptosis of cells receiving combined IL-3 and TEL/PDGF{beta}R signals. We demonstrate that TEL/PDGF{beta}R expression augmented IL-3–induced activation of PKB, STAT5, ERK1/2, p38, and JNK1/2. Inhibition of neither phosphoinositide-3 kinases nor p38 MAPKs reduced the inhibition of IL-3–driven proliferation observed when TEL/PDGF{beta}R was expressed. However, inhibition of MEKs or JNKs partially reversed the combined inhibitory effects of TEL/PDGF{beta}R and IL-3 on proliferation and survival. These results suggest that the combination of TEL/PDGF{beta}R and IL-3–induced signals activate apoptosis through ERK and JNK MAPK-dependent pathways. Given that in vivo hematopoietic cells are in contact with a variety of cytokines, our results have important implications for cellular responses in the pathogenesis of CMML.


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